Enzyme Linked To Loss Of Muscle Mass In Older Adults, Study Finds

(Posted on Monday, December 18, 2023)

This article is part of a broad series on recent advances in the science and medicine of longevity and aging. The series covers a range of topics, including musculoskeletal health. Expect more articles on bone and muscle regeneration to follow.

Muscle is what keeps us moving. It is integral to athletic performance, yes, but also to everyday activities. This is all the more relevant as we age: past 30, we begin to lose 3% to 5% of our muscle mass per decade. Such age-related loss of muscle, called “sarcopenia”, in technical speak, can lead to frailty and immobility down the line, both of which worsen quality of life. Researchers with the Blau Lab at Stanford University are taking things into their own hands, piecing together the various causes of muscle decline with age. Their latest findings, published in Science, suggest that nerve-muscle connections may be a key part of the equation, and that re-establishing these connections helps bring back and maintain muscle and strength. 

Muscle Maintenance: Stem Cells and “Gerozymes”

Whether deliberate, as is the case with exercise, or accidental, as is the case with injury, our muscles inevitably sustain damage through the course of our lives. Small amounts of damage are healthy, and promote muscles to grow. Too much damage, and the muscle is overwhelmed, leading to extended rest and recovery. 

In either scenario, muscle stem cells play a central role in repairing damaged tissue and building new fibers. The stem cells sit in our muscle tissue, where they wait to be called into action. When muscle is damaged, it sends an alarm signal by releasing various proteins and hormones. As soon as the signals reach the muscle stem cells, they mobilize and travel to the site of injury. Once there, they develop into muscle cells and divide rapidly to replace the damaged cells or to fuse damaged tissue back together. 

Previous research by the Blau Lab uncovered the important role of a molecule called prostaglandin E2 (PGE2) in this chain of events. It is one of the chemical messengers synthesized and released by stressed muscle tissue in response to injury and is particularly closely involved in the recruitment of the stem cells. Mice engineered to lack the receptor that allows for prostaglandin E2 signaling displayed noticeably slower muscle regeneration. And injured muscle treated with a single dose of prostaglandin E2 displayed accelerated repair and improved recovery of total strength. 

In a follow-up study, the Blau Lab discovered that, as we age, our muscles begin to accumulate an enzyme called 15-hydroxyprostaglandin dehydrogenase (15-PGDH). As it turns out, this enzyme degrades prostaglandin E2, getting in the way of the molecule’s usual muscle-regenerating properties. Indeed, stimulating 15-PGDH in young mice led to a shrinkage of muscle fibers and a loss of strength. The atrophied muscles resembled those normally seen in older mice. In contrast, blocking 15-PGDH for a month in old mice returned their strength and largely reversed age-associated loss of muscle; they were 15-20% stronger after the treatment and their muscle fibers looked like those of young mice. 

Prior to their research, 15-hydroxyprostaglandin dehydrogenase had not been implicated in aging. The researchers dubbed the enzyme a “gerozyme”, a portmanteau made up of the Greek root for old, “gero”, and “enzyme”.

Restoring Nerve-Muscle Connectivity 

Although the earlier work by Dr. Helen Blau and her colleagues made it clear that 15-PGDH is integral to the degeneration of muscle tissue seen in older adults, the exact mechanisms surrounding the process remain unknown. In this latest study, the researchers returned to find out. 

Aside from containing elevated levels of 15-PGDH, older muscles also contain fewer nerve-muscle connections, known as “neuromuscular junctions”. These junctions help the brain tell our muscles what to do and when to do it. Every time you take a step, for example, your brain signals your muscles to contract and relax, allowing you to walk. The same thing happens when you brush your teeth or drink a glass of water. But as neuromuscular junctions weaken, so do we — the muscles as a whole shrink, and the force with which they can contract begins to fade. 

The researchers were curious to see if this loss of connections between muscles and motor neurons was related to an increase in 15-PGDH. To find out, they induced an injury in the sciatic nerve of mice that reduced the number of neuromuscular junctions. Compared to other, non-injured mice of the same age, those with sciatic damage showed elevated levels of the gerozyme. Treating the injured mice with a small-molecule drug that inhibits 15-PGDH helped recover lost motor neurons and, by extension, helped re-establish lost neuromuscular junctions. These changes at the muscular level were reflected by quicker recovery of force. 

Crucially, a similar regenerative effect was seen in old mice treated with an inhibitor of 15-PGDH; areas that had lost nerve supplies as a consequence of age began to see a return of motor neuron activity and a subsequent increase in nerve-muscle connections. Again, the changes were accompanied by a significant increase in strength and force of the muscles. 

Besides aged or injured muscles, certain diseases of the nervous system are also defined by clusters of 15-PGDH. Reducing the levels of the gerozyme in these diseases may promise to alleviate symptoms and trigger the regeneration of muscles and neuromuscular junctions. 

This study is the first to show that damaged motor neurons can be regenerated through treatment with a drug. Although there have yet to be any human trials of the inhibitor of 15-PGDH, a company co-founded by Dr. Blau, Epirium Bio, has obtained licenses for patents that focus on improving muscle strength through 15-PGDH inhibition. More research is sure to follow. 

Takeaways

Loss of muscle and strength is a serious concern for aging adults. Not only does the decline of muscle mass have the potential to decrease quality of life, it also increases the risk of injury. The latest work by researchers at the Blau Lab adds to their prior findings on the mechanisms underlying age-related muscle decline. The gerozyme 15-PGHD increases in muscle tissue with age and alongside nerve injuries. In both cases, it hampers recovery and weakens muscle function. Blocking the enzyme speeds up recovery and even regenerates lost nerve-muscle connections, resulting in healthier muscle fibers and renewed strength. 

This article was originally published on Forbes and can be read online here.